tbuckley/cabot-search huggingface dataset:
Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases
Authors: Kenta Mosallanejad, Stephanie N. Kennedy, Kristin M. Bahleda, Kailey M. Slavik, Wen Zhou, Apurva A. Govande, Dustin C. Hancks, Philip J. Kranzusch, Jonathan C. Kagan
Journal: Science Immunology (2023)

The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA–reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.
Estimating Temporally Variable Selection Intensity from Ancient DNA Data
Authors: Zhangyi He, Xiaoyang Dai, Wenyang Lyu, Mark Beaumont, Feng Yu
Journal: Molecular Biology and Evolution (2023)

Novel technologies for recovering DNA information from archaeological and historical specimens have made available an ever-increasing amount of temporally spaced genetic samples from natural populations. These genetic time series permit the direct assessment of patterns of temporal changes in allele frequencies and hold the promise of improving power for the inference of selection. Increased time resolution can further facilitate testing hypotheses regarding the drivers of past selection events such as the incidence of plant and animal domestication. However, studying past selection processes through ancient DNA (aDNA) still involves considerable obstacles such as postmortem damage, high fragmentation, low coverage, and small samples. To circumvent these challenges, we introduce a novel Bayesian framework for the inference of temporally variable selection based on genotype likelihoods instead of allele frequencies, thereby enabling us to model sample uncertainties resulting from the damage and fragmentation of aDNA molecules. Also, our approach permits the reconstruction of the underlying allele frequency trajectories of the population through time, which allows for a better understanding of the drivers of selection. We evaluate its performance through extensive simulations and demonstrate its utility with an application to the ancient horse samples genotyped at the loci for coat coloration. Our results reveal that incorporating sample uncertainties can further improve the inference of selection.
A microRNA signature for risk-stratification and response prediction to FOLFOX-based adjuvant therapy in stage II and III colorectal cancer
Authors: Keisuke Okuno, Raju Kandimalla, Marta Mendiola, Francesc Balaguer, Luis Bujanda, Carlos Fernandez-Martos, Jorge Aparicio, Jaime Feliu, Masanori Tokunaga, Yusuke Kinugasa, Joan Maurel, Ajay Goel
Journal: Molecular Cancer (2023)

Clinical decision-making for adjuvant chemotherapy, which includes the selection of the most appropriate patient subgroups and optimal treatment regimens, remains the most pressing challenge in managing patients with stage II and III colorectal cancer (CRC) [1,2].For stages III CRC patients, 6 months of FOLFOXbased adjuvant chemotherapy has long been the standard of care treatment following radical surgery of the primary tumor [3][4][5][6][7]; however, given the inherent toxicity of these drugs and inadequate response to these treatments, there is a significant unmet clinical need to identify improved treatment regimens and develop better predictive biomarkers that allow an improved patient selection.Although changes to mono-therapy or shortening the treatment duration from 6 months to 3 months have been attempted in various clinical trials [8,9], these results are still controversial.Furthermore, 35-40% of stage III patients experience tumor recurrence following adjuvant chemotherapy [3-7]; hence, they are unnecessarily exposed to the toxicity and expense of these drugs without any tangible therapeutic benefit.These patients
Second Oral SERD Shines in ER+ Breast Cancer
Journal: Cancer Discovery (2023)

The first data from the phase II SERENA-2 trial look promising for the investigational oral selective estrogen receptor degrader camizestrant. Compared with standard fulvestrant, it significantly prolonged progression-free survival in postmenopausal women with advanced estrogen receptor-positive, HER2-negative breast cancer. Camizestrant also bested fulvestrant in subgroup analyses of patients who previously received a CDK4/6 inhibitor, had visceral metastases, or had ESR1 mutations.
Association Between Early Return to School Following Acute Concussion and Symptom Burden at 2 Weeks Postinjury
Authors: Christopher G. Vaughan, Andrée-Anne Ledoux, Maegan D. Sady, Ken Tang, Keith Owen Yeates, Gurinder Sangha, Martin H. Osmond, Stephen B. Freedman, Jocelyn Gravel, Isabelle Gagnon, William Craig, Emma Burns, Kathy Boutis, Darcy Beer, Gerard Gioia, Roger Zemek, Candice McGahern, Angelo Mikrogianakis, Ken Farion, Karen Barlow, Alexander S Dubrovsky, Willem Meeuwisse, William Meehan, Yael Kamil, Miriam Beauchamp, Blaine Hoshizaki, Peter Anderson, Brian L. Brooks, Michael Vassilyadi, Terry Klassen, Michelle Keightley, Lawrence Richer, Carol Dematteo, Nick Barrowman, Mary Aglipay, Anne Grool
Journal: JAMA Network Open (2023)

Importance Determining how the timing of return to school is related to later symptom burden is important for early postinjury management recommendations. Objective To examine the typical time to return to school after a concussion and evaluate whether an earlier return to school is associated with symptom burden 14 days postinjury. Design, Setting, and Participants Planned secondary analysis of a prospective, multicenter observational cohort study from August 2013 to September 2014. Participants aged 5 to 18 years with an acute (&amp;amp;lt;48 hours) concussion were recruited from 9 Canadian pediatric emergency departments in the Pediatric Emergency Research Canada Network. Exposure The independent variable was the number of days of school missed. Missing fewer than 3 days after concussion was defined as an early return to school. Main Outcomes and Measures The primary outcome was symptom burden at 14 days, measured with the Post-Concussion Symptom Inventory (PCSI). Symptom burden was defined as symptoms status at 14 days minus preinjury symptoms. Propensity score analyses applying inverse probability of treatment weighting were performed to estimate the relationship between the timing of return to school and symptom burden. Results This cohort study examined data for 1630 children (mean age [SD] 11.8 [3.4]; 624 [38%] female). Of these children, 875 (53.7%) were classified as having an early return to school. The mean (SD) number of days missed increased across age groups (5-7 years, 2.61 [5.2]; 8-12 years, 3.26 [4.9]; 13-18 years, 4.71 [6.1]). An early return to school was associated with a lower symptom burden 14 days postinjury in the 8 to 12-year and 13 to 18-year age groups, but not in the 5 to 7-year age group. The association between early return and lower symptom burden was stronger in individuals with a higher symptom burden at the time of injury, except those aged 5 to 7 years. Conclusions and Relevance In this cohort study of youth aged 5 to 18 years, these results supported the growing belief that prolonged absences from school and other life activities after a concussion may be detrimental to recovery. An early return to school may be associated with a lower symptom burden and, ultimately, faster recovery.
The PhenX Toolkit: standard measurement resources for cancer outcomes and survivorship research
Authors: Larissa Nekhlyudov, Keith Bellizzi, Andrew Galligan, Bellinda King-Kallimanis, Deborah K Mayer, Christine Miaskowski, Talya Salz, Catherine McCarty, Lisa Cox, Christine Hill, Tabitha P Hendershot, Deborah R Maiese, Carol M Hamilton
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract This brief report introduces the Cancer Outcomes and Survivorship domain in the PhenX Toolkit (consensus measures for Phenotypes and eXposures), which includes 15 validated measurement protocols for cancer survivorship research that were recommended for inclusion in this publicly available resource. Developed with input from the scientific community, the domain provides researchers with well-established measurement protocols for evaluating physical and psychological effects, financial toxicity, and patient experiences with cancer care. The PhenX Toolkit, funded by the National Human Genome Research Institute since 2007, is an online resource that provides high-quality standard measurement protocols for a wide range of research areas (eg, smoking cessation, harm reduction and biomarkers, and social determinants of health). Use of the PhenX Cancer Survivorship Outcomes and Survivorship domain can simplify the selection of measurement protocols, data sharing, and comparisons across studies investigating the cancer survivorship experience.
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma
Authors: Gaurav Kumar Pandey, Nick Landman, Hannah K. Neikes, Danielle Hulsman, Cor Lieftink, Roderick Beijersbergen, Krishna Kalyan Kolluri, Sam M. Janes, Michiel Vermeulen, Jitendra Badhai, Maarten van Lohuizen
Journal: Cell Reports Medicine (2023)

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.
Roadmap for Achieving Universal Antiretroviral Treatment
Authors: Simiso Sokhela, Samanta Lalla-Edward, Mark J. Siedner, Mohammed Majam, Willem Daniel Francois Venter
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Modern antiretroviral therapy safely, potently, and durably suppresses human immunodeficiency virus (HIV) that, if left untreated, predictably causes acquired immunodeficiency syndrome (AIDS), which has been responsible for tens of millions of deaths globally since it was described in 1981. In one of the most extraordinary medical success stories in modern times, a combination of pioneering basic science, innovative drug development, and ambitious public health programming resulted in access to lifesaving, safe drugs, taken as an oral tablet daily, for most of the world. However, substantial challenges remain in the fields of prevention, timely access to diagnosis, and treatment, especially in pediatric and adolescent patients. As HIV-positive adults age, treating their comorbidities will require understanding the course of different chronic diseases complicated by HIV-related and antiretroviral toxicities and finding potential treatments. Finally, new long-acting antiretrovirals on the horizon promise exciting new options in both the prevention and treatment fields.
Comparison of Cardiovascular Procedure Rates in Patients With Supplementary vs Basic Insurance in Switzerland
Authors: Tristan Struja, Flurina Suter, Sabine Rohrmann, Daniel Koch, Beat Mueller, Philipp Schuetz, Alexander Kutz
Journal: JAMA Network Open (2023)

Importance Switzerland’s mandatory health insurance provides universal coverage, but residents can opt for supplementary private insurance for nonessential, nonvital amenities. It is debated whether people with supplementary private insurance receive overtreatment due to financial incentives. Objective To assess whether incidence rates of cardiovascular procedures in people with supplementary private insurance are higher than in those with basic insurance only. Design, Setting, and Participants A population-based weighted cohort comparative effectiveness study, using administrative claims data from Switzerland assessing incidence rates (IRs), was conducted in adults undergoing a nonemergency cardiovascular inpatient procedure from January 1, 2012, to December 31, 2020. Analysis included primary or secondary discharge procedure codes for 1 of the following: percutaneous transluminal coronary angioplasty (PTCA), left atrial appendage (LAA) occlusion, patent foramen ovale (PFO) closure, transcatheter aortic valve replacement (TAVR), mitral valve clip implantation, cardiac pacemaker implantation, and atrial fibrillation/atrial flutter ablation. Exposures Supplementary private health insurance. Main Outcomes and Measures Incidence rates of cardiovascular procedures between insurance groups calculated by negative binomial regression adjusted by inverse probability weights. Results Of 590 919 admissions (median age, 68 years; IQR, 57-77 years), 55.5% male, 15.7% non-Swiss nationality), 70.1% had basic insurance only. Independent of insurance status, IR for all cardiovascular procedures steadily increased over the study years. In general, people with supplementary private insurance received cardiovascular procedures more frequently (IR ratio [IRR], 1.11; 99% CI, 1.10-1.11) than people with basic insurance only. There was also an increase for every procedure: PTCA (IRR, 1.12; 99% CI, 1.12-1.13), LAA closure (IRR, 1.15; 99% CI, 1.13-1.16), mitral valve clip implantation (IRR, 1.08; 99% CI, 1.07-1.09), TAVR (IRR, 1.04; 99% CI, 1.03-1.06), PFO closure (IRR, 1.01; 99% CI, 1.00-1.02), pacemaker implantation (IRR, 1.08; 99% CI, 1.07-1.09), and atrial fibrillation/atrial flutter ablation (IRR, 1.12; 99% CI, 1.11-1.12). Sensitivity analyses, including side procedures, stratification by length of stay, and propensity score matching, suggested robustness of the results. Conclusions and Relevance This study found an association between supplementary private insurance and a higher likelihood of receiving nonemergency cardiovascular procedures. Whether this higher rate of procedures in people with supplementary private insurance is based on clinical reasoning or due to financial incentives warrants further exploration.
Harnessing the Power of Electronic Health Records and Genomics for Drug Discovery
Authors: Kristi Krebs, Lili Milani
Journal: The Annual Review of Pharmacology and Toxicology (2023)

A long-standing recognition that information from human genetics studies has the potential to accelerate drug discovery has led to decades of research on how to leverage genetic and phenotypic information for drug discovery. Established simple and advanced statistical methods that allow the simultaneous analysis of genotype and clinical phenotype data by genome- and phenome-wide analyses, colocalization analyses with quantitative trait loci data from transcriptomics and proteomics data sets from different tissues, and Mendelian randomization are essential tools for drug development in the postgenomic era. Numerous studies have demonstrated how genomic data provide opportunities for the identification of new drug targets, the repurposing of drugs, and drug safety analyses. With an increase in the number of biobanks that enable linking in-depth omics data with rich repositories of phenotypic traits via electronic health records, more powerful ways for the evaluation and validation of drug targets will continue to expand across different disciplines of clinical research.
<i>Cis</i>- and<i>Trans</i>-variations of Stearoyl-CoA Desaturase Provide New Insights into the Mechanisms of Diverged Pattern of Phenotypic Plasticity for Temperature Adaptation in Two Congeneric Oyster Species
Authors: Chaogang Wang, Ao Li, Rihao Cong, Haigang Qi, Wei Wang, Guofan Zhang, Li Li
Journal: Molecular Biology and Evolution (2023)

The evolution of phenotypic plasticity plays an essential role in adaptive responses to climate change; however, its regulatory mechanisms in marine organisms which exhibit high phenotypic plasticity still remain poorly understood. The temperature-responsive trait oleic acid content and its major gene stearoyl-CoA desaturase (Scd) expression have diverged in two allopatric congeneric oyster species, cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. In this study, genetic and molecular methods were used to characterize fatty acid desaturation and membrane fluidity regulated by oyster Scd. Sixteen causative single-nucleotide polymorphisms (SNPs) were identified in the promoter/cis-region of the Scd between wild C. gigas and C. angulata. Further functional experiments showed that an SNP (g.-333C [C. gigas allele] >T [C. angulata allele]) may influence Scd transcription by creating/disrupting the binding motif of the positive trans-factor Y-box factor in C. gigas/C. angulata, which mediates the higher/lower constitutive expression of Scd in C. gigas/C. angulata. Additionally, the positive trans-factor sterol-regulatory element-binding proteins (Srebp) were identified to specifically bind to the promoter of Scd in both species, and were downregulated during cold stress in C. gigas compared to upregulated in C. angulata. This partly explains the relatively lower environmental sensitivity (plasticity) of Scd in C. gigas. This study serves as an experimental case to reveal that both cis- and trans-variations shape the diverged pattern of phenotypic plasticity, which provides new insights into the formation of adaptive traits and the prediction of the adaptive potential of marine organisms to future climate change.
Linguistic Analysis Identifies Emergent Biomaterial Fabrication Trends for Orthopaedic Applications
Authors: Ryan C. Locke, Hannah M. Zlotnick, Brendan D. Stoeckl, George W. Fryhofer, Jonathan H. Galarraga, Abhishek P. Dhand, Miltiadis H. Zgonis, James L. Carey, Jason A. Burdick, Robert L. Mauck
Journal: Advanced Healthcare Materials (2023)

The expanse of publications in tissue engineering (TE) and orthopedic TE (OTE) over the past 20 years presents an opportunity to probe emergent trends in the field to better guide future technologies that can make an impact on musculoskeletal therapies. Leveraging this trove of knowledge, a hierarchical systematic search method and trend analysis using connected network mapping of key terms is developed. Within discrete time intervals, an accelerated publication rate for anatomic orthopedic tissue engineering (AOTE) of osteochondral defects, tendons, menisci, and entheses is identified. Within these growing fields, the top-listed key terms are extracted and stratified into evident categories, such as biomaterials, delivery method, or 3D printing and biofabrication. It is then identified which categories decreased, remained constant, increased, or emerged over time, identifying the specific emergent categories currently driving innovation in orthopedic repair technologies. Together, these data demonstrate a significant convergence of material types and descriptors used across tissue types. From this convergence, design criteria to support future research of anatomic constructs that mimic both the form and function of native tissues are formulated. In summary, this review identifies large-scale trends and predicts new directions in orthopedics that will define future materials and technologies.
Improvement in Disease Activity in Refractory Juvenile Dermatomyositis Following Abatacept Therapy
Authors: Rodolfo V. Curiel, William Nguyen, Gulnara Mamyrova, Derek Jones, Alison Ehrlich, Kathleen A. Brindle, Shahriar Haji‐Momenian, Robert Sheets, Hanna Kim, Olcay Y. Jones, Lisa G. Rider
Journal: Arthritis & Rheumatology (2023)

This open-label, 24-week study was conducted to evaluate the safety and efficacy of abatacept in patients with refractory juvenile dermatomyositis (DM).
Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem
Authors: Shahrzad Ghazisaeidi, Milind M. Muley, Michael W. Salter
Journal: The Annual Review of Pharmacology and Toxicology (2023)

The study of chronic pain continues to generate ever-increasing numbers of publications, but safe and efficacious treatments for chronic pain remain elusive. Recognition of sex-specific mechanisms underlying chronic pain has resulted in a surge of studies that include both sexes. A predominant focus has been on identifying sex differences, yet many newly identified cellular mechanisms and alterations in gene expression are conserved between the sexes. Here we review sex differences and similarities in cellular and molecular signals that drive the generation and resolution of neuropathic pain. The mix of differences and similarities reflects degeneracy in peripheral and central signaling processes by which neurons, immune cells, and glia codependently drive pain hypersensitivity. Recent findings identifying critical signaling nodes foreshadow the development of rationally designed, broadly applicable analgesic strategies. However, the paucity of effective, safe pain treatments compels targeted therapies as well to increase therapeutic options that help reduce the global burden of suffering.